Implantable drug-delivery devices, and apparatus and methods for filling the devices

ABSTRACT

In various embodiments, a tool is employed in filling a drug-delivery device. The tool may include, for example, a needle that is admitted through a fill port of the drug-delivery device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of, and incorporatesherein by reference in their entireties, U.S. Provisional PatentApplication Nos. 61/051,422, which was filed on May 8, 2008; 61/197,752,which was filed on Oct. 30, 2008; 61/197,817, which was filed on Oct.30, 2008; and 61/198,126, which was filed on Nov. 3, 2008.

TECHNICAL FIELD

In various embodiments, the invention relates to implantabledrug-delivery devices and to apparatus and methods for filling suchdevices.

BACKGROUND

Medical treatment often requires the administration of a therapeuticagent (e.g., medicament, drugs, etc.) to a particular part of apatient's body. As patients live longer and are diagnosed with chronicand/or debilitating ailments, the likely result will be an increasedneed to place even more protein therapeutics, small-molecule drugs, andother medications into targeted areas throughout the patient's body.Some maladies, however, are difficult to treat with currently availabletherapies and/or require administration of drugs to anatomical regionsto which access is difficult to achieve.

A patient's eye is a prime example of a difficult-to-reach anatomicalregion, and many vision-threatening diseases, including retinitispigmentosa, age-related macular degeneration (AMD), diabeticretinopathy, and glaucoma, are difficult to treat with many of thecurrently available therapies. For example, oral medications can havesystemic side effects; topical applications may sting and engender poorpatient compliance; injections generally require a medical visit, can bepainful, and risk infection; and sustained-release implants musttypically be removed after their supply is exhausted (and generallyoffer limited ability to change the dose in response to the clinicalpicture).

Another example is cancer, such as breast cancer or meningiomas, wherelarge doses of highly toxic chemotherapies, such as rapamycin,bevacizumab (e.g., AVASTIN), or irinotecan (CPT-11), are typicallyadministered to the patient intravenously, which may result in numerousundesired side effects outside the targeted area. Yet another example isdrug delivery to the knee, where drugs often have difficulty penetratingthe avascular cartilage tissue for diseases such as osteoarthritis.

Implantable drug-delivery devices, which may have a refillable drugreservoir, a cannula for delivering the drug, etc., generally allow forcontrolled delivery of pharmaceutical solutions to a specified target.As drug within the drug reservoir depletes, the physician can refill thereservoir with, for example, a syringe, while leaving the deviceimplanted within the patient's body. This approach can minimize thesurgical incision needed for implantation and typically avoids future orrepeated invasive surgery or procedures.

A variety of challenges, however, are associated with refillabledrug-delivery devices. For example, while a fill port may be located ona surface of the device to facilitate post-implantation access, the factthat the device is installed within the patient's anatomy may make suchaccess uncomfortable for the patient and risk damage to the device. Suchdifficulties are especially problematic if the device is refilledmanually. When filling the drug reservoir using a handheld syringe, forexample, it is possible to generate large pressures in the syringe,particularly when small volumes are involved and the syringe plunger isof small diameter. These high pressures may damage the device and/orcause improper drug expulsion. Also, trying to refill the drug-deliverydevice with a handheld single-barrel syringe can require several cyclesof needle insertion and withdrawal as different fluids are removed andinjected into the device. This may cause stress for both the patient andthe doctor, and creates unnecessary wear on the fill port.

A need exists, therefore, for improved implantable drug-deliverydevices, and apparatus and methods for filling such devices.

SUMMARY OF THE INVENTION

In various embodiments, the present invention features apparatus andmethods for emptying, rinsing, and filling, in situ, a drug reservoir ofa drug-delivery device implanted within a patient's body via one or moreself-sealing, needle-accessible fill ports. The drug-delivery device maybe, for example, an implantable drug-delivery pump. The apparatusgenerally contain features, and the methods typically involve steps,that allow the emptying, rinsing, and filling to occur in a manner thatminimizes the risk of damage to the pump, and thereby maximizes itseffective lifetime. For example, in one embodiment, a dedicated refillinstrument allows multiple fluids to be controlled and directed througha single fill port of the drug-delivery pump and with only a singleneedle insertion. In addition, the refilling process may be automated soas to protect pump components from potential damage and ensure reliableand repeatable refilling.

In various embodiments, the fill port(s) of the implantable pump itselfcontain various features that, either alone or in combination, promotethe reliable and repeatable refilling of the implantable drug-deliverypump. For example, as described herein, the fill port(s) may containfeatures that prevent the backflow of drug from the drug reservoirthrough the fill port.

In general, in one aspect, embodiments of the invention feature animplantable drug-delivery pump. The pump includes a drug reservoir and,in fluid communication therewith, a fill port that includes anelastomeric plug. The plug extends at least partially through anaperture in a wall of the fill port. The pump also includes means forenhancing retainment of the plug within the aperture (e.g., grooves orthreads, or other features that promote mechanical interlocking, in theaperture). In various embodiments, the pump also includes a parylenecoating in or over the aperture.

In general, in another aspect, embodiments of the invention featureanother implantable drug-delivery pump. Again, this pump includes a drugreservoir and, in fluid communication therewith, a fill port thatincludes an elastomeric plug extending at least partially through anaperture in a wall of the fill port. Moreover, the pump also includes acheck valve, closeable over the aperture, for preventing backflow fromthe reservoir through the fill port. The check valve may include a pairof parylene flaps or a single parylene flap closable over the aperture.

In either pump, the wall through which the aperture of the fill port isformed may be the same as a wall that surrounds, at least partially, thedrug reservoir. Alternatively, tubing may be employed to connect theaperture of the fill port to the drug reservoir. In various embodiments,the plug is made of silicone. The fill port may include a needle guidefor guiding a needle therethrough. Furthermore, the fill port may have ageometry that is compatible only with needles having a complementarygeometry.

In general, in yet another aspect, embodiments of the invention featurean implantable drug-delivery pump that includes a drug reservoir, acannula for conducting liquid from the reservoir to a target site, anelectrolyte chamber, an expandable diaphragm that separates the chamberand the reservoir and that provides a fluid barrier therebetween, and aplurality of fill ports for providing external access to at least one ofthe reservoir or the chamber. For example, a first fill port may provideexternal access to the reservoir and a second fill port may provideexternal access to the chamber. Alternatively or in addition, at leasttwo fill ports may each provide external access to the reservoir and/orat least two fill ports may each provide external access to the chamber.

In general, in still another aspect, embodiments of the inventionfeature a tool for refilling an implantable drug-delivery pump, such asa pump as described above. The tool includes first and secondindependent fluid channels, a fluid reservoir in fluid communicationwith the first fluid channel, first and second pumps each fluidlycoupled to one of the fluid channels, and means for engaging a fill portof the implantable drug-delivery pump. The first pump may be configuredto apply positive pressure to the first fluid channel so as to drivefluid from the fluid reservoir therethrough, and the second pump may beconfigured to apply negative pressure to the second fluid channel. Forits part, the engaging means may be a needle that is configured forinsertion into the fill port. The needle may have a lumen in fluidcommunication with the first and second fluid channels.

In various embodiments, the tool further includes a third independentfluid channel, a second fluid reservoir in fluid communicationtherewith, and a third pump fluidly coupled to the third fluid channel.In such a case, the third pump may be configured to apply positivepressure to the third fluid channel so as to drive fluid from the secondfluid reservoir therethrough.

The tool may also include governing circuitry that prevents fluidpressure at an outlet of the needle lumen from exceeding a predefinedlevel. First and second valves, responsive to the governing circuitry,may also be included to control fluid flow through the first and secondfluid channels, respectively. Moreover, the tool may include a bubbledetector and/or a degasser in at least one of the first, second, orthird fluid channels. The bubble detector may be, for example, anultrasonic bubble detector, an optical bubble detector, a thermal bubbledetector, or an electrical bubble detector.

In another embodiment, the needle features first and second lumenstherethrough. The first and second lumens may be fluidly isolated fromeach other. The first lumen may communicate with the first fluidchannel, and the second lumen may communicate with the second fluidchannel.

In general, in still another aspect, embodiments of the inventionfeature a method of filling an implantable drug-delivery pump having adrug chamber. In accordance with the method, a tool is first provided.The tool includes first and second independent fluid channels, and afluid reservoir in fluid communication with the first fluid channel. Thetool may be coupled to a fill port of the implantable drug-deliverypump, and then be used to purge the drug chamber and subsequently pumpfluid from the fluid reservoir into the drug chamber via the first fluidchannel without exceeding a maximum pressure in the drug chamber.

In various embodiments, the tool is coupled to the fill port by means ofa needle that has a lumen in fluid communication with the first andsecond fluid channels. The purging step may include pumping fluid fromthe fluid reservoir into the drug chamber via the needle and the firstfluid channel and thereafter suctioning the fluid from the drug chambervia the needle and the second fluid channel. In another embodiment, thetool further includes a third independent fluid channel and a secondfluid reservoir in fluid communication therewith, and the purging stepinvolves pumping fluid from the second fluid reservoir into the drugchamber via the needle and the third fluid channel, and thereaftersuctioning the fluid from the drug chamber via the needle and the secondfluid channel.

These and other objects, along with advantages and features of theembodiments of the present invention herein disclosed, will become moreapparent through reference to the following description, theaccompanying drawings, and the claims. Furthermore, it is to beunderstood that the features of the various embodiments described hereinare not mutually exclusive and can exist in various combinations andpermutations, even if not made explicit herein.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention. In the followingdescription, various embodiments of the present invention are describedwith reference to the following drawings, in which:

FIG. 1A schematically illustrates, in cross-section, an implantabledrug-delivery device in accordance with one embodiment of the invention;

FIG. 1B schematically illustrates, in cross-section, an implantabledrug-delivery device in accordance with another embodiment of theinvention;

FIG. 2 schematically illustrates an implantable drug-delivery device,having multiple fill ports, in accordance with yet another embodiment ofthe invention;

FIG. 3A schematically illustrates, in cross-section, the internalstructure of a fill port in accordance with one embodiment of theinvention, as it is pierced by a refill needle;

FIG. 3B schematically illustrates, in cross-section, the internalstructure of a fill port that is connected by tubing to a drug reservoirin accordance with one embodiment of the invention, as the fill port ispierced by a refill needle;

FIGS. 4A-4D schematically illustrate, in cross-section, the internalstructure of various fill ports in accordance with further embodimentsof the invention;

FIGS. 5A-5E schematically illustrate, in cross-section, a process formanufacturing yet another variant of a fill port in accordance with oneembodiment of the invention;

FIGS. 6A-6D schematically illustrate, in cross-section, the internalstructure of various fill ports having needle stops in accordance withembodiments of the invention;

FIG. 7 schematically illustrates, in cross-section, the internalstructure of a fill port having a needle guide in accordance with oneembodiment of the invention;

FIG. 8 schematically illustrates, in cross-section, the internalstructure of a fill port having a pair of flaps as a check valve inaccordance with one embodiment of the invention, as drug is deliveredthereto;

FIG. 9 schematically illustrates, in cross-section, the internalstructure of a fill port having a single flap as a check valve inaccordance with one embodiment of the invention, as drug is deliveredthereto;

FIG. 10 schematically illustrates a tool for refilling an implantabledrug-delivery device in accordance with one embodiment of the invention;

FIG. 11 schematically illustrates a tool, having a single lumen refillneedle, inserted into a fill port of an implantable drug-delivery devicein accordance with one embodiment of the invention;

FIG. 12 schematically illustrates a tool, having a double lumen refillneedle, inserted into a fill port of an implantable drug-delivery devicein accordance with one embodiment of the invention; and

FIG. 13 schematically illustrates the tool of FIG. 10 coupled to aninput and display device in accordance with one embodiment of theinvention.

DESCRIPTION

In general, embodiments of the present invention pertain todrug-delivery pumps implantable within a patient's body, such as, forexample, within the patient's eye or brain, and to apparatus and methodsfor refilling those pumps. In certain embodiments, the implantabledrug-delivery pumps combine small size and a refillable drug reservoir.The small size minimizes discomfort from the drug-delivery pump to thepatient, while the refillable reservoir allows the pump to be refilledin situ, rather than having to be replaced. As such, a fluid, such as asolution of a drug, can be supplied to the patient over extended periodsof time.

Embodiments of the invention may be employed in connection with varioustypes of implantable drug-delivery pumps. FIGS. 1A and 1B schematicallyillustrate two variations of one such implantable drug-delivery pump 100(namely, an exemplary electrolytic pump 100) implanted within apatient's eye 104. The pump 100 may instead, however, be implanted inother portions of a patient's body. For example, it may be implanted inthe sub-arachnoid space of the brain to provide chemotherapy or toprovide another type of treatment for the brain (e.g., by dosing thebrain's parenchyma directly), or near a tumor in any portion of thepatient's body to provide chemotherapy, or in a pancreas that does notrespond well to glucose to provide agents (e.g., proteins, viralvectors, etc.) that will trigger insulin release, or in the knee toprovide drugs that will treat osteoarthritis or other cartilagediseases, or near the spine to provide pain medications oranti-inflammatories, or elsewhere. As illustrated in FIGS. 1A and 1B,embodiments of the pump 100 may include two main components: a pair ofchambers 108, 112 surrounded, at least in part, by a wall 115, and acannula 120. As illustrated in FIG. 1A, the wall 115 that surrounds thechambers 108, 112 may include or consist of a stand-alone parylene film116 and, thereover, a separate protection shell 128 made of a relativelyrigid biocompatible material (e.g., medical-grade polypropylene).Alternatively, as illustrated in FIG. 1B, the wall 115 may correspondonly to the protective shell 128, which may be coated with parylene. Thetop chamber 108 defines a drug reservoir that, when being used to treata patient, may contain the drug to be administered in liquid form. Forits part, the bottom chamber 112 may contain a liquid that, whensubjected to electrolysis, evolves a gaseous product. For example, thatliquid may be water, which may be electrolytically separated by anapplied voltage into hydrogen gas and oxygen gas. Alternatively, asother examples, the electrolyte liquid may be a saline solution (i.e.,NaCl and H₂O) or a solution that contains either magnesium sulfate orsodium sulfate. In one embodiment, the two chambers 108, 112 areseparated by a corrugated diaphragm 124. In other words, the diaphragm124 provides a fluid barrier between the two chambers 108, 112. Like thestand-alone film 116, the diaphragm 124 may be constructed from, forexample, parylene.

As illustrated in FIG. 1A, the stand-alone film 116 may act as an outerbarrier for the drug reservoir 108 and the protective shell 128 mayprovide a hard surface against which the film 116 exerts pressure. Insuch a case, the shell 128 may be perforated to allow for eye, brain, orother bodily fluid movement. Alternatively, as illustrated in FIG. 1B,the protective shell 128 may itself act as the outer barrier for thedrug reservoir 108 and be unperforated. In both embodiments depicted inFIGS. 1A and 1B, the protective shell 128 may prevent outside pressurefrom being exerted on the drug reservoir 108. As illustrated in FIG. 1A,a bottom portion 126 (i.e., a floor 126) of the protective shell 128 mayinclude suture holes 130. Similarly, although not shown in either FIG.1A or FIG. 1B, the cannula 120 may also include suture holes along itssides. The suture holes 130 may be employed in suturing (i.e.,anchoring) the pump 100 in place in the patient's body.

As also illustrated in FIG. 1A, to provide power to the pump 100 and toenable data transmission therewith, a battery and control circuitry 132may be embedded (e.g., hermetically sealed) under the chambers 108, 112(i.e., between a bottom portion of the stand-alone parylene film 116 ofthe drug reservoir 108 and the floor 126 of the protective shell 128),and an induction coil 136 may be integrated in the protective shell 128(e.g., by injection molding). FIG. 1B more clearly illustrates ahermetic case 135 for housing the battery and conventional controlcircuitry 132, but, for simplicity, does not depict the componentshoused therein. The hermetic case 135 may be made from biocompatiblemetals (e.g., titanium) or metal alloys. The bottom of the hermetic case135 may be flat, or it may be concave to help the implantable pump 100fit on the patient's eye 104.

In one embodiment, the induction coil 136 permits wireless (e.g.,radio-frequency) communication with an external device (e.g., ahandset). The handset may be used to send wireless signals to thecontrol circuitry 132 in order to program, reprogram, operate,calibrate, or otherwise configure the pump 100. In one embodiment, thecontrol circuitry 132 communicates electrically with electrolysiselectrodes 134 in the electrolyte chamber 112 by means of metalinterconnects (vias) 138 spanning a bottom portion of the electrolytereservoir 112. The electrolysis electrodes 134 may be made from, forexample, platinum, gold, and/or other metal(s). As further describedbelow, the control circuitry 132 controls the pumping action of the pump100, including the below-described closed-loop control process.

In one embodiment, as illustrated in FIG. 1A, the cannula 120 connectsthe drug chamber 108 to a check valve 140 inserted at the site ofadministration. Alternatively, or in addition, as illustrated in FIG.1B, the check valve 140 may be integral with and located at a proximalend of the cannula 120 (i.e., at the end closest to the drug reservoir108). One or more flow sensors 144 for monitoring the flow of thedrug—and thereby enabling the measurement of drug volume—through thecannula 120 may be associated with one or more of a proximal, middle, ordistal portion of the cannula 120. Optionally, as illustrated in FIG.1A, a pressure sensor 148 may also be integrated at a distal end of thecannula 120 (i.e., at the end furthest from the drug reservoir 108) inorder to measure pressure at the site of administration (e.g., theintravitreal chamber, shoulder capsule, knee capsule, cerebralventricals, spinal canal, etc.). In one embodiment, the pressure sensor148 provides feedback to the control circuitry 132 so that the flow ofdrug may be metered by a closed-loop control process. For example,increased pressure in the drug target region may cause a decrease in theflow of drug from the pump 100.

As illustrated in FIG. 1A, the cannula 120 may be an extension of thestand-alone parylene film 116. Alternatively, as illustrated in FIG. 1B,the cannula 120 may be a separate component coupled to the protectiveshell 128. For example, a proximal end of the cannula 120 may beinserted through a fluid connection port formed in the protective shell128 and bonded thereto by way of, e.g., a biocompatible epoxy glue 150.A silicone sheath 154 may be placed around a portion of the cannula 120(see FIG. 1B), but this is optional (see FIG. 1A).

In one embodiment, as illustrated in FIG. 1A, a fill port 152 isassembled with the drug reservoir 108 and sealed by a sealant (e.g., abiocompatible epoxy) 156 to the stand-alone film 116 and protectiveshell 128. In yet another embodiment, as illustrated in FIG. 1B, a holemay be formed through the protective shell 128 and the fill port 152featured therein. In still another embodiment, the fill port 152 may beformed elsewhere on the pump 100 and connected to the drug reservoir 108through tubing. For example, the fill port 152 may be molded frombiocompatible materials, coupled to a matching notch on the hermeticcase 135, and connected to the drug reservoir 108 through the tubing. Inone embodiment, the tubing is inserted through a fluid connection portformed in a wall surrounding the drug reservoir 108 and bonded theretoby way of a biocompatible epoxy glue. In either case, as describedfurther below, the fill port 152 is in fluid communication with the drugreservoir 108 and permits an operator of the pump 100 (e.g., aphysician) to refill the drug reservoir 108 in situ (e.g., while thepump 100 is implanted within the patient's eye 104). In general, thedrug reservoir 108 can be refilled by inserting a refill needle into andthrough the fill port 152.

In various embodiments, the main parts of the pump 100 (i.e., the pairof chambers 108, 112 and the cannula 120) are amenable to monolithicmicrofabrication and integration using multiple parylene layerprocesses. The fill port 152, the protective shell 128, and othercomponents may be assembled with the pump 100 after the microfabricationsteps.

In operation, when current is supplied to the electrolysis electrodes134, the electrolyte evolves gas, expanding the corrugated diaphragm 124(i.e., moving the diaphragm upwards in FIGS. 1A and 1B) and forcingliquid (e.g., drug) to be conducted out of the drug reservoir 108,through the cannula 120, and out the distal end thereof to the targetedsite of administration. The corrugations or other folds in theexpandable diaphragm 124 permit a large degree of expansion, withoutsacrificing volume within the drug reservoir 108 when the diaphragm 124is relaxed. When the current is stopped, the electrolyte gas condensesback into its liquid state, and the diaphragm 124 recovers itsspace-efficient corrugations.

In some embodiments, with reference to FIG. 2, the implantable pump 100includes a plurality of fill ports 152. For example, the pump 100 mayinclude a first, single fill port 152A that provides external access tothe drug reservoir 108 and a second, single fill port 152B that providesexternal access to the electrolyte chamber 112. In this way, eitherchamber 108, 112 may be refilled when depleted (e.g., as sensed by thecontrol circuitry 132). Alternatively, the pump 100 may include (i) twoor more fill ports 152A providing external access to the drug reservoir108 and no or a single fill port 152B providing external access to theelectrolyte chamber 112, or (ii) two or more fill ports 152B providingexternal access to the electrolyte chamber 112 and a single fill port152A (or no fill port) providing external access to the drug reservoir108, or (iii) two or more fill ports 152A providing external access tothe drug reservoir 108 and two or more fill ports 152B providingexternal access to the electrolyte chamber 112. In one embodiment,multiple fill ports 152 for a single chamber 108, 112 facilitate theemptying, rinsing, and/or filling of the chamber 108, 112 (e.g., toextract trapped air, etc.), with one fill port receiving new fluid asexisting fluid exits another fill port. The multiple fill ports 152A,152B may be integrated with the pump 100 as described above (e.g.,formed through the protective shell 128; coupled to the pump 100 inanother location and connected to the drug reservoir 108 or electrolytechamber 112, as the case may be, through tubing; etc.).

FIG. 3A schematically illustrates the internal structure of a fill port152, in accordance with one embodiment of the invention, as it ispierced by a refill needle 200. The fill port 152 is illustrated in FIG.3A as being in fluid communication with the drug reservoir 108. However,as described above, the fill port 152 may instead be in fluidcommunication with the electrolyte chamber 112. Moreover, rather thanbeing in direct contact with the drug reservoir 108 or electrolytechamber 112, the fill port 152 may instead be connected thereto throughintermediary tubing 202, as illustrated in FIG. 3B. Accordingly, it willbe understood by one of ordinary skill in the art that the followingdescription of the various embodiments of the fill port 152 and of thevarious embodiments of refilling the drug reservoir 108 using the fillport 152 also apply equally to a fill port 152 that is in fluidcommunication with the electrolyte chamber 112 (either directly orthrough use of the intermediary tubing 202) and to methods of refillingthe electrolyte chamber 112 using the fill port 152.

As illustrated in FIGS. 3A and 3B, one embodiment of the fill port 152includes an elastomeric plug 204 that is molded inside a hollowstructure 208 defined by a wall 224 of the fill port 152. Where the fillport 152 is in fluid communication with the drug reservoir 108 withoutthe use of the tubing 202 (FIG. 3A), the hollow structure 208 may infact be an aperture that spans the thickness of the protective shell 128and/or the stand-alone film 116. As shown in FIGS. 3A and 3B, theelastomeric plug 204 may extend at least partially through the aperture208. In one embodiment, the diameter and thickness of the elastomericplug 204 is generally less than 3 mm.

The elastomeric plug 204 may be, for example, a silicone plug 204 (asindicated in FIGS. 3A and 3B). More generally, however, the plug 204 maybe made from any material (e.g., soft plastic) that that can bepunctured with the needle 200 and that is capable of re-sealing itselfupon removal of the needle 200. Moreover, the self-sealing material ofthe plug 204 may be able to withstand multiple punctures by the needle200, and may be biocompatible. In addition to silicone, materials fromwhich the plug 204 may be manufactured include, but are not limited to,polydimethylsiloxane (“PDMS”), parylene C, parylene HT, polycarbonates,polyolefins, polyurethanes, copolymers of acrylonitrile, copolymers ofpolyvinyl chloride, polyamides, polysulphones, polystyrenes, polyvinylfluorides, polyvinyl alcohols, polyvinyl esters, polyvinyl butyrate,polyvinyl acetate, polyvinylidene chlorides, polyvinylidene fluorides,polyimides, polyisoprene, polyisobutylene, polybutadiene, polyethylene,polyethers, polytetrafluoroethylene, polychloroethers,polymethylmethacrylate, polybutylmethacrylate, polyvinyl acetate,nylons, cellulose, gelatin, and porous rubbers.

In one embodiment, to form the silicone plug 204, uncured siliconerubber is directly injected inside the hollow structure 208 and cured inplace. The self-sealing properties of the silicone rubber allow theneedle 200 to be inserted into and withdrawn from the fill port 152without causing any permanent leaks.

The fill port 152 illustrated in FIGS. 3A and 3B includes a smooth-boreaperture 208. In some embodiments, however, the fill port 152 furtherincludes means for enhancing retainment of the plug 204 within theaperture 208. For example, as shown in the fill port 152 illustrated inFIG. 4A, threads, grooves or other features 212 facilitating mechanicalinterlocking may be machined on or molded into the walls 224 that definethe aperture 208 to keep the plug 204 secured in place. These features212 increase the sealing surface area and also mechanically anchor theplug 204 in place.

In addition, where the plug 204 is made of a polymer (e.g., silicone)that is capable of leaching or absorbing drugs that come into contactwith it, the fill port 152 may be coated with a biocompatible polymer(e.g., parylene) so that less drug is exposed to the polymer. Thecoating 216 also aids to minimize the possibility of leaking at theplug/support interface. The parylene coating 216 may be applied before,after, or both before and after the formation of the plug 204 so thatthe parylene coating 216 is applied inside, over, or both inside andover the aperture 208, respectively. For example, the fill port 152depicted in FIG. 4B features a silicone plug 204 molded inside asmooth-bore aperture 208 that has a single parylene coating 216 insidethe aperture 208, the fill port 152 depicted in FIG. 4C features asilicone plug 204 molded inside a smooth-bore aperture 208 that has asingle parylene coating 216 over (and only partially inside) theaperture 208, and the fill port 152 depicted in FIG. 4D features asilicone plug 204 molded inside a smooth-bore aperture 208 that has adual parylene coating 216 (both inside and over the aperture 208).

In yet another embodiment, the parylene coating 216 may be appliedinside in aperture 208 and over a bottom portion thereof, but not over atop portion of the aperture 208. Such a structure for the fill port 152is illustrated in FIG. 5E, while FIGS. 5A-5D schematically illustratethe steps in an exemplary process for manufacturing the structuredepicted in FIG. 5E. In greater detail, with reference first to FIG. 5A,a parylene coating 216 is first applied to the aperture 208 of the fillport 152 and, thereafter, the plug 204 is formed therein. Then, asillustrated in FIG. 5B, the top surface of the fill port 152 is maskedby applying a further segment 226 of silicone thereto. Subsequently, asecond parylene coating 216 may be applied (FIG. 5C) and the furthersegment 226 of silicone stripped away from the fill port 152 (FIG. 5D),leaving the structure depicted in FIG. 5E. Advantageously, the use ofthe silicone segment 226 prevents the second parylene coating 216 fromcovering the top surface of the aperture 208. One reason for which sucha structure is desirable is that it prevents the second parylene coating216 from being dragged into the plug 204 during needle 200 insertion.Dragging the parylene coating 216 into the plug 204 may, for example,damage the fill port 152 and lead to the leakage of fluid therefrom.

With reference now to FIGS. 6A-6D, in some cases it is desirable to havea needle stop 220 positioned within the fill port 152. As illustrated,the stop 220 may extend at least partially into the aperture 208. Thestop 220 may be integrally formed with the wall 224 of the fill port 152or may be a separately manufactured piece that is secured to the wall224 by, for example, by gluing the stop 220 to the wall 224 with anepoxy or other suitable adhesive. In this way, the progress of therefill needle 200 into the fill port 152 halts when a tip of the needle200 contacts the stop 220. This prevents the needle 200 from beinginserted too far into the pump 100, which could cause damage thereto.

The stop 220 may take the form of a mechanical plate (e.g., asillustrated in FIGS. 6A and 6D), a filter (e.g., as illustrated in FIG.6C), a bend (e.g., as illustrated in FIG. 6B), or any number of otherstructures whose shape is suitable for carrying out the functions of thestop 220 described herein. Moreover, as illustrated in FIGS. 6A and 6D,the top surface of the stop 220 may be flat. Alternatively, the topsurface of the stop 152 may be cup-shaped or concave. In this way, thestop 220 may also aid in preventing the refill needle 200 fromcontacting, and possibly penetrating, one of the sidewalls 224 definingthe aperture 208.

The fill port 152 and the needle stop 220 thereof can also be designedso that only certain needles 200 can be used to access the drugreservoir 108. In other words, the fill port 152 may be designed to havea geometry that is compatible only with needles 200 having acomplementary geometry. For example, as illustrated in FIG. 6D, an exithole of the needle 200 only matches with an access channel 228 when theneedle 200 is fully inserted to the needle stop 220. And, as illustratedin FIGS. 6A-6C, the exit hole of the needle 200 only matches with anarea of the aperture 208 not occupied by the plug 204 when the needle200 is fully inserted to the needle stop 220.

In general, the stop 220 of the fill port 152 may be constructed of anyrelatively rigid and mechanically robust material, or combinations ofmaterials, that has/have the requisite mechanical strength forperforming the functions of the stop 220 described herein. For example,the stop 220 may be constructed of a metal, a hard (e.g., fullycross-linked or reinforced) plastic, a composite material, or acombination thereof. More specific examples of materials for the stop220 include a thick layer of PDMS, polyimide, polypropylene,polyaryletheretherketone (“PEEK”), polycarbonate, acetyl film (e.g.,acetyl copolymer), polyoxymethylene plastic (e.g., DELRIN), gold,stainless steel, nickel, and/or chrome. The stop 220 may (but need notnecessarily) be biocompatible.

Because the fill port 152 may be of relatively small size, it may bedesirable, in some embodiments, for the fill port 152 to also include aneedle guide to ensure that the needle 200 is inserted substantiallystraight into the fill port 152. While there is some room for error, toolarge an entry angle may cause the needle 200 to strike the supportstructure for the fill port 152 (i.e., the wall 224), and to misspenetrating the elastomeric plug 204. As illustrated in FIG. 7, theneedle guide 232 may be conically shaped, or may have another shape. Inaddition, the needle guide 232 may be integrally formed with the fillport 152, or it may be removable and be placed on top of the fill port152, and mechanically or magnetically locked thereto, just prior to therefilling procedure.

In another embodiment, the implantable drug-delivery pump 100 alsoincludes a check valve, for example within the drug reservoir 108 orwithin the intermediary tubing 202 and closeable over the aperture 208,for preventing backflow from the reservoir 108 through the fill port152. The check valve may also rectify the flow of drug from the needle200 into the drug reservoir 108 and reduce the possibility of leakage.In one embodiment, the check valve opens as liquid is pushed into thedrug reservoir 108, and thereafter closes.

Two exemplary check valve designs are depicted in FIGS. 8 and 9. Theillustrated check valves 300 include one (FIG. 9) or two (FIG. 8) flaps304A, 304B of a biocompatible polymer, such as parylene. The flap(s)304A, 304B may be bonded to the bottom surface of the fill port's wall224 using, for example, an adhesive, thermal bonding, ultrasonicbonding, laser welding, etc. As illustrated in FIG. 8, the flaps 304A,304B are forced apart (or a single flap 304 is displaced from theaperture 208, as illustrated in FIG. 9), as liquid is injected into thedrug chamber 108 from the refill needle 200. After withdrawal of theneedle 200, the pressure exerted on the flap(s) 304A, 304B by theinjected liquid will keep the check valve 300 closed over the aperture208, thus preventing any backflow of liquid through the fill port 152.While in FIGS. 8 and 9 the fill ports 152 are shown to have an uncoatedsmooth-bore aperture 208 design, it will be understood by one ofordinary skill in the art that the fill ports 152 may in fact have anyof the above-described configurations (e.g., have threaded or groovedsidewalls, be parylene-coated, etc.).

Embodiments of the invention also facilitate filling or refilling thedrug reservoir 108 of the implantable drug-delivery device 100 describedabove. Through a fill port 152 of the pump 100, any remaining liquid maybe removed, the drug reservoir 108 washed, and the new drug injected.Accordingly, embodiments of the invention may feature an external toolthat interfaces with the implantable drug-delivery pump 100 tofacilitate automated refilling of the drug reservoir 108. Filling orrefilling of the drug reservoir 108 may occur while the pump 100 isimplanted within the patient's body (e.g., within the patient's eye 104)and may involve procedures for emptying, washing, and filling orrefilling the drug chamber 108. As described below, these processes maybe performed using a tool that features either a single-lumen or adual-lumen needle.

A tool for interfacing to and refilling a drug reservoir 108 asdescribed herein may have two, three, or more independent fluidchannels. For example, the tool 400 depicted in FIG. 10 includes threeindependent fluid channels 404, 408, 412. The first channel 404 is influid communication with a first pump 416 that handles the drug 420. Thesecond channel 408 is in fluid communication with a second pump 424 thathandles a rinse solution 428. The third channel 412 uses vacuum suction432 to remove or aspirate fluid waste 436 from the drug reservoir 108.Fluid flow through all three channels 404, 408, 412 can be effectedusing standard mechanical pumping technologies (e.g., gear, diaphragm,peristaltic, syringe, etc.). The flows can also be pneumaticallycontrolled through the application of pressure or vacuum to theindividual channels 404, 408, 412. As illustrated in FIG. 10, thesethree fluid channels 404, 408, 412 may be interfaced to a flow-switchingor valving system 440 and ultimately terminate in the needle 200, whichis used to pierce the elastomeric plug 204 of the fill port 152 andaccess the drug reservoir 108.

In addition, in one embodiment, one, more, or all of the channels 404,408, 412 include a bubble detector 442 and/or an in-line degasser 446.Each of the detector 442 and the degasser 446 may be located upstream ofthe valving system 440, as depicted in FIG. 10. Alternatively, one orboth of the detector 442 and degasser 446 may in fact be locateddownstream of the valving system 440. As such, the order in which thevarious components of the tool 400 are shown to be placed in FIG. 10 isnon-limiting.

In one embodiment, the bubble detector 442 serves to detect gas in itsrespective channel 404, 408, 412. The presence of gas inside the drugreservoir 108 could cause the pump 100 to malfunction. Advantageously,upon detection by a bubble detector 442 of a gas bubble in one of thechannels, 404, 408, 412, the detector 442 may signal (e.g., to governingcircuitry 444, described further below) the presence of such gas. Thefilling/refilling of the drug reservoir 108 may then be stopped, theneedle 200 removed from the fill port 152, and the tool 400 flushed toremove any and all gas.

A bubble detector 442 may be implemented through a variety of means,including, but not limited to, ultrasonic, optical, thermal, orelectrical. For example, an ultrasonic bubble detector 442 may be placedin proximity, but not in contact, with fluid flowing through a channel404, 408, 412, transmit ultrasonic energy through the flowing fluid, andsense the amount of energy transmitted therethrough. The amount ofenergy transmitted through the fluid will change when there is gaspresent in the fluid. Suitable ultrasonic bubble detectors 442 may beprovided by, for example, Introtek International of Edgewood, N.Y.;Zevek, Inc. of Salt Lake City, Utah; and Cosense, Inc. of

An optical detector 442 may also be placed in proximity, but not incontact, with fluid flowing through a channel 404, 408, 412, shine light(e.g., infra-red light) through the flowing fluid, and sense the amountof light transmitted therethrough. Again, the amount of lighttransmitted through the fluid will change when there is gas present inthe fluid.

For its part, a thermal detector 442 may be placed in contact with (orin proximity to, but not in contact with) the fluid. The thermaldetector 442 may then heat (e.g., through use of a heater) fluid flowingpassed the detector 442 and sense the temperature of the fluid at, forexample, a downstream location. The different thermal properties of aflowing fluid, as opposed to a flowing fluid comprising gas, will resultin different temperatures for each being sensed downstream. Accordingly,the temperature sensed downstream may indicate the presence or absenceof gas in the fluid. Suitable thermal bubble detectors 442 may beprovided by, for example, Sensirion AG of Switzerland.

Finally, an electrical detector 442 may measure some electrical propertyof the fluid flowing through the channel 404, 408, 412. For example, theelectrical detector 442 may measure the dielectric constant,resistivity, etc. of the flowing fluid. The reading may provide anindication of the presence, or absence, of gas in the fluid.

For its part, a degasser 446 may automatically remove any and all gasfrom its respective channel 404, 408, 412. For example, the degasser 446may be implemented as a semi-permeable membrane (e.g., permeable to gas,but not to fluid) in a wall of its respective channel 404, 408, 412. Gaspresent in that channel would then be expelled from the channel throughthe membrane. In addition, a vacuum may be applied to the membrane walloutside the channel 404, 408, 412 to speed up the gas removal process.

While FIG. 10 depicts a tool 400 having three independently controlledfluid channels 404, 408, 412, it is possible in some cases, asmentioned, to use fewer. For example, instead of using a dedicated washsolution 428 to rinse the drug reservoir 108, the drug solution 420 canitself be used for that purpose. In these embodiments, two independentfluid channels 404, 412—one (404) for infusing the drug 420 and a second(412) for aspirating liquid 436 out of the reservoir 108—will suffice.

The tool 400 may also include governing circuitry 444 to control andactuate the first and second pumps 416, 424, the vacuum suction 432, theflow-switching or valving system 440, the bubble detectors 442, and/orthe vacuums interfacing with the degassers 446. The control logicunderlying the governing circuitry 444 may be implemented as anysoftware program, hardware device, or combination thereof that iscapable of achieving the functionality described herein. For example,the governing circuitry 440 may be an application-specific integratedcircuit (ASIC) or a field programmable gate array (FPGA). Alternatively,the governing circuitry 440 may be one or more general-purposemicroprocessors (e.g., any of the PENTIUM microprocessors supplied byIntel Corp.) programmed using any suitable programming language orlanguages (e.g., C++, C#, java, Visual Basic, LISP, BASIC, PERL, etc.).Suitable control programming is straightforwardly implemented by thoseof skill in the art without undue experimentation.

In one embodiment, the tool 400 is configured for careful control of therefill process so that the pressure inside the drug reservoir 108 (i.e.,the fluid pressure at an outlet of the needle 200) does not exceed agiven, critical value. This prevents damage to the pump 100 and alsoprevents unwanted ejection of drug through the cannula 120 and into thepatient. The pressure inside the drug reservoir 108 may be maintainedbelow the critical value in several ways. For example, if liquid isinfused into the drug reservoir 108 pneumatically, then the governingcircuitry 444 may keep injection pressure below the critical value. Apressure-release valve can also be used in the pneumatic drive as afail-safe mechanism. As another example, if the liquid is infused usingmechanical pumps (e.g., gear, diaphragm, peristaltic, syringe, etc.),the pressure inside the drug reservoir 108 may be controlled byintegrating a pressure sensor at the point of highest hydraulicpressure. The governing circuitry 444 may monitor the pressure sensorand employ a conventional feedback system to prevent the pressure atthis point from exceeding the critical value. As still another example,the governing circuitry 444 may meter the volume of fluid delivered tothe drug reservoir 108 to prevent overfilling. In general, it is onlywhen the reservoir 108 reaches full capacity that the internal pressurebegins to rise.

For its part, the needle 200 may be a single lumen needle, or the needle200 may include first and second lumens therethrough. In the case of thesingle-lumen needle 200, the needle lumen will be in fluid communicationwith each of the three fluid channels 404, 408, 412, as illustrated inFIG. 11, or, where a separate wash solution 428 and pump 424 thereforare not used, with just each of the first and third channels 404, 412.In the case of the dual-lumen needle 200, the first and second lumensmay be fluidly isolated from one another. As illustrated in FIG. 12, thefirst lumen may be in fluid communication with the first and secondchannels 404, 408 (or with just the first channel 404 where the separatewash solution 428 and pump 424 therefor are not used) and the secondlumen may be in fluid communication with the third channel 412.

Exemplary methods of filling and/or refilling the drug reservoir 108 ofthe pump 100 may be understood with reference to FIGS. 11 and 12. Withreference first to FIG. 11, in this example, the entire refill processis conducted through a single needle 200 (having a single lumen) and asingle fill port 152 of the implantable drug-delivery pump 100. Allthree valves A, B, and C in the valving system 440 are initially closedas the needle 200 is inserted into the fill port 152. As described abovewith reference to FIGS. 6A-6D, the needle 200 may be advanced into thefill port 152 until its distal tip contacts the stop 220 and its exitport is in fluid communication with the drug chamber or reservoir 108.At that point, the governing circuitry 444 may cause valve C to beopened and any fluid in the reservoir 108 may be removed using suction.In particular, the governing circuitry 444 may cause the vacuum suctionpump 432 to apply negative pressure to the third fluid channel 412 so asto aspirate any fluid in the drug reservoir 108 into the waste reservoir436. The vacuum suction pump 432 may then be shut off and valve C closedby the governing circuitry 444. The circuitry 444 may then cause valve Ato be opened and the second pump 424 to apply positive pressure to thesecond fluid channel 408 so as to drive a wash solution from the washreservoir 428 through the second channel 408 and the needle 200 lumeninto the drug chamber 108. Once sufficient wash solution 428 has beenpumped into the drug reservoir 108, the governing circuitry 444 maycause the second pump 424 to be shut off and valve A to be closed. Thesetwo steps can be repeated as many times as necessary for effectiveness.Alternatively, during these two steps, valves A and C in the valvingsystem 440 may constantly be kept open, the second pump 424 maycontinuously pump wash solution into the drug reservoir 108, and thevacuum suction pump 432 may continuously remove fluid from the drugreservoir 108. In this way, the washing and emptying of the drugreservoir 108 occurs in tandem. In still another embodiment, where aseparate wash solution 428 and pump 424 therefor are not used (asdescribed above), the drug reservoir 108 of the pump 100 may instead berinsed, during this purging step, with the drug solution 420. To do so,valve B in the valving system 440 and the first pump 416 are operated bythe governing circuitry 444 in a manner similar to that just describedfor valve A and the second pump 424, respectively.

After the final waste-removal step is complete and the drug chamber 108has been purged, the governing circuitry 444 may close valves A and Cand open valve B to fill the drug reservoir 108 with the drug solution420. In particular, once valve B is open, the governing circuitry 444may cause the first pump 416 to apply positive pressure to the firstfluid channel 404 so as to drive drug from the reservoir 420, throughthe first channel 404 and needle 200 lumen, into the drug reservoir 108of the implanted drug-delivery pump 100. Once a sufficient amount of thedrug solution 420 has been pumped into the drug reservoir 108, thegoverning circuitry 444 may cause the first pump 416 to be shut off andvalve B to be closed.

During the entire process described with reference to FIG. 11, the flowrates of the various fluids and the various pressures of injection andsuction may all be controlled by the governing circuitry 444. Forexample, the governing circuitry 444 may monitor or track the pressurein the drug chamber 108, as described above, to prevent it fromsurpassing a critical value.

With reference now to FIG. 12, in a second example, the entire refillprocess is conducted through a single needle 200 (having a dual lumenstructure) and a single fill port 152 of the implantable drug-deliverypump 100. The two lumens of the needle 200 provide two parallel,isolated paths for fluid to travel in and out of the drug reservoir 108.As indicated in FIG. 12, one of these lumens may be in fluidcommunication with the third channel 412 and be dedicated to aspirationof fluid from the drug reservoir 108, while the other lumen may be influid communication with the first and second channels 404, 408 (or justthe first channel 404 where a separate wash solution 428 and pump 424therefor are not used) and be used to infuse liquid (i.e., drug and/orwash solutions 420, 428) into the drug reservoir 108.

All three valves A, B, and C in the valving system 440 are initiallyclosed as the needle 200 is inserted into the fill port 152. Then, oncethe needle 200 has been properly inserted, the governing circuitry 444opens valve C and any fluid in the drug reservoir 108 is removed usingsuction. The governing circuitry 444 then pumps the drug reservoir 108full of the wash solution 428 by opening valve A. Again, during thislatter step, the suction can either be turned off and multiplesuction/wash steps performed (by alternately opening and closing valvesA and C), or the suction can be left on to perform a continuous rinse ofthe drug reservoir 108. In either case, once the final waste-removalstep is complete and the drug chamber 108 has been purged, valves A andC may be closed by the governing circuitry 444 and valve B opened tofill the drug reservoir 108 with the drug solution 420.

Once again, the flow rates of the various fluids and the variouspressures of injection and suction may all be controlled by thegoverning circuitry 444, for example to prevent the pressure internal tothe drug reservoir 108 from surpassing a critical value. Moreover, asdescribed above, the separate wash solution 428 and pump 424 thereformay be omitted and the drug solution 420 instead used as the wash/rinsesolution.

FIG. 13 depicts the tool 400 coupled to an input and display device 448in accordance with one embodiment of the invention. More specifically, acartridge 452, which may house the pumps 416, 424, 432, the reservoirs420, 428, 436, the channels 404, 408, 412, and the valving system 440depicted in FIG. 10, is coupled at one end to the input and displaydevice 448 and at the other end to the needle 200. The governingcircuitry 444 is typically part of the input and display device 448, butmay in other embodiments be part of the cartridge 452 and interface withthe input and display device 448. As illustrated, the input and displaydevice 448 features one or more input buttons 456 and a display screen460. The display screen 460 may display, for example, the drug and/orthe dosage thereof being administered, the cycle at which the tool 400is at (e.g., emptying, rinsing, filling, standby or ready), the statusof the implantable pump 100 (e.g., full, empty), the pressure inside thedrug reservoir 108, or any other information of interest to an operatorof the tool 400. For their part, the input buttons 456 allow an operatorto control the tool 400 (e.g., to select the dosage of the drug to beadministered, the mode of operation, the parameters relating to pumpingand purging, and the drug to be loaded into the drug reservoir 108), tonavigate through various options presented by the display screen 460,etc.

As will be understood by one of ordinary skill in the art, the tool 400described with reference to FIGS. 10-13 may also be employed to empty,rinse, and/or fill/refill the electrolyte chamber 112. One manner ofdoing so is to simply replace the drug solution 420 with an appropriateelectrolyte solution, and then operate the tool 400 as described above.

Accordingly, as described herein, an operator may rapidly and accuratelyfill or refill the drug reservoir 108 and/or the electrolyte chamber 112of the implantable drug-delivery pump 100 in situ via one or moreself-sealing, needle-accessible fill ports 152. Moreover, as described,this may be done in a manner that minimizes the risk of damage to thepump 100, and thereby maximizes its effective lifetime.

Having described certain embodiments of the invention, it will beapparent to those of ordinary skill in the art that other embodimentsincorporating the concepts disclosed herein may be used withoutdeparting from the spirit and scope of the invention. Accordingly, thedescribed embodiments are to be considered in all respects as onlyillustrative and not restrictive.

1. An implantable drug-delivery pump, comprising: a drug reservoir; afill port comprising an elastomeric plug extending at least partiallythrough an aperture in a wall, the fill port being in fluidcommunication with the drug reservoir; and internal threads in theaperture for engaging complementary threads on the plug and therebyenhancing retainment of the plug within the aperture.
 2. The pump ofclaim 1 further comprising a parylene coating in or over the aperture.3. The pump of claim 1, wherein the fill port further comprises a needleguide for guiding a needle therethrough.
 4. The pump of claim 3, whereinthe fill port has a geometry compatible only with needles having acomplementary geometry.
 5. The pump of claim 1, wherein the plugconsists essentially of silicone.
 6. The pump of claim 1, wherein thewall surrounds, at least partially, the drug reservoir.
 7. The pump ofclaim 1 further comprising a tube connecting the aperture of the fillport to the drug reservoir.
 8. An implantable drug-delivery pump,comprising: a drug reservoir; a fill port comprising an elastomeric plugextending at least partially through an aperture in a wall, the fillport being in fluid communication with the drug reservoir; and a checkvalve, closable over the aperture, wherein in a closed state the checkvalve prevents backflow from the reservoir through the fill port whileallowing forward flow into the reservoir.
 9. The pump of claim 8,wherein the check valve comprises at least one flap closable over theaperture.
 10. The pump of claim 9, wherein the at least one flapcomprises parylene.
 11. The pump of claim 8, wherein the fill portfurther comprises a needle guide for guiding a needle therethrough. 12.The pump of claim 11, wherein the fill port has a geometry compatibleonly with needles having a complementary geometry.
 13. The pump of claim8, wherein the plug consists essentially of silicone.
 14. The pump ofclaim 8, wherein the wall surrounds, at least partially, the drugreservoir.
 15. The pump of claim 8 further comprising a tube connectingthe aperture of the fill port to the drug reservoir.
 16. An implantabledrug-delivery pump, comprising: a drug reservoir; a cannula forconducting liquid from the reservoir to a target site; an electrolytechamber having at least two electrolysis electrodes therein; anexpandable diaphragm separating the chamber and the reservoir andproviding a fluid barrier therebetween; and a plurality of fill portsfor providing external access to at least one of the reservoir or thechamber, wherein the fill port comprises an elastomeric plug extendingat least partially through an aperture in a wall that comprises internalthreads therein for engaging complementary threads on the plug andthereby enhancing retainment of the plug within the aperture.
 17. Thepump of claim 16, wherein a first fill port provides external access tothe reservoir and a second fill port provides external access to thechamber.
 18. The pump of claim 16, wherein at least two fill ports eachprovide external access to the reservoir.
 19. The pump of claim 16,wherein at least two fill ports each provide external access to thechamber.